Hydrogenation of kojic acid to hexahydrokojic acid



United HYnRoGENArroN or KOJIC ACID T rmxnnvnnoaonc ACID Jay S. Buckley,in, Groton, Russell D. Drinkard, New London, and Paul D. Thomas, Groton,Conn., assignors to Chas. Pfizer & Co., Inc., Brooklyn, N. Y., acorporation of Delaware No Drawing. Application August 5, 1955 SerialNo. 526,768

4 Claims. (Cl. 260-3453) nlication Serial No. 526,767, filed August 5,1955.

Hexahydrokojic acid is most readily obtained by the catalytichydrogenation of kojic acid or its salts. This process is illustrated bythe following equation.

Kojic acid is a fermentation product obtained by the cultivation ofcertain species of Aspergillus under appropriate conditions. Kojic acidis acidic by virtue of its enolic hydroxyl group while the hydrogenationproduct, hexahydrokojic acid, is a neutral, cyclic polyalkanol.

Various processes have been suggested in the past for the preparation ofhexahydrokojic acid from kojic acid. However, none has beensatisfactory. Previous processes involve low pressure catalytichydrogenation in the presence of a noble metal catalyst such as platinumor palladium. These processes are unsatisfactory from several points ofview both with regard to their laboratory use and their commercialapplication. First, it has not been possible to produce purehexahydrokojic acid by these processes. Mixtures containing partiallyhydrogenated kojic acid along with the hexahydro derivative wereobtained. Separation of these mixtures was very diflicult and costly,and as a result, pure hexahydrokojic acid was unknown prior to thedevelopment of the valuable process of this invention.

The crude mixtures of the prior art methods are not satisfactoryintermediates for chemical. syntheses such as the preparation of esters,ethers, and resins as described in the copending applications referredto above. In general, it is desirable to have a pure or at least areproducible product as a starting material for such processes. Afurther shortcoming of prior art processes for the preparation ofhexahydrokojic acid is that noble metal catalysts are required. Suchcatalysts are expensive and recovery of the metal from the spentcatalyst is necessary. It is therefore an object of this invention toprovide a process for the preparation of hexahydrokojic acid which isconvenient and economical to operate and which gives a pure andreproducible product.

It has now been found that kojic acid is smoothly and rapidlyhydrogenated to hexahydrokojic acid in the presence of a nickel catalystat elevated temperatures and States Patent G ice superatmosphericpressures. Pressures in the range 500-2000 p. s. i. are readily obtainedwith ordinary high pressure equipment and yield satisfactory results inthe instant process. Analytically pure hexahydrokojic acid isconsistently produced by this process. Various types of nickel catalystscan be employed including supported nickel catalysts such as nickel onkieselguhr and the socalled Raney nickel catalysts which are a veryfinely divided form of nickel prepared by the treatment of analuminum-nickel alloy with strong alkali to dissolve away the aluminum.The preparation of such catalysts is well known in the art. Although itis customary to recover the metal from spent nickel catalysts as is donewith noble metal catalysts, recovery is not usually a critical economicfactor.

The hydrogenation can be carried out either in an aqueous suspension orsolution or in an organic solvent. Suitable solvents include the loweralkanols such as methanol, ethanol, and isopropanol; tertiary aminessuch as those of the aliphatic, hydrolylated aliphatic, aromatic and theliquid heterocyclic series including triethylamine,dimethylethanolamine, triethanol amine, dimethylaniline, and pyridine,and certain other materials such as dimethylformamide. The choice ofsolvent is not a critical factor in the process as long as all of thecomponents are compatible and the solvent itself is not affected by thehydrogenation conditions. It is not necessary that the kojic aciddissolve completely in the solvent employed. Slurries or suspensions ofkojic acid may be employed as long as the kojic acid is partiallysoluble. However, it is preferred to use water as the solvent since thefire hazard involved with the use of finely divided metal catalysts withinflammable solvents eliminated. The process is usually carried out in abatch-wise fashion wherein the solvent and the kojic acid is charged toan autoclave equipped for heating and agitation, either by stirring orrocking, the catalyst is added, and the mixture hydrogenated until threemoles of hydrogen is absorbed per mole of kojic acid charged. Hydrogenabsorption ceases at this point which corresponds to the theoreticalamount. Recovery of the product involves filtration of the catalyst andwashing of it with fresh solvent, evaporation of the solvent, and, insome cases, distillation of the crude product. When the product is notdistilled, it is customary to dry it thoroughly in a high vacuum priorto use or storage.

A preferred embodiment of this valuable invention yields hexahydrokojicacid of analytical quality directly and avoids the distillation stepwhich is difficult and costly to carry out on a commercial scale. Theessential features of this embodiment involve carrying out thehydrogenation at as low a temperature as possible, prompt separation ofthe catalyst, and treatment of the supernatant liquid with decolorizingcarbon. The use of as low a temperature as possible is important sincecarbonization is a problem at higher temperatures. It has been foundthat it is most satisfactory to operate in the range -110 C. However,with very active catalysts temperatures as low as room temperature orabout 30 C. may be employed. Above C. carbonization is quite severe andpurification of the product is a problem. A further factor in obtaininga pure product is to minimize the contact time of the hydrogenationsolution with the catalyst since the catalyst also seems to causediscoloration of the solution.

As was indicated above, it is also possible to prepare hexahydrokojicacid by the hydrogenation of salts of kojic acid. Either the metal orthe amine salts may be employed. Examples of the metal salts include thesodium, potassium, lithium, calcium and barium salts. Amine salts withsuch strongly basic amines as triethyldifficulties.

. r 3 amine, trimethylamine, and tri'ethanolarnine as.well as theammonium salt may be used. Use of salts of kojic acid in the instantprocess is however attended'by certain Kojic acid is somewhat unstable ahigh pHs and a greater amount of decomposition with theattendantpurific'atio'n problem is encountered. Furthermore, since'the'product, hexahydrokojieacid, is a neutral compound, the basecorresponding to the original salt charged is liberated during thehydrogenation. A step must therefore be included in the recovery processto allow for separation of the liberated base. The primary advantageofusing a salt of kojic acid or an alkaline material with the kojic acidin some cases is to improve thejsolubility of the kojic acid in thesolvent selected.

In one specific embodiment of this valuable invention, kojic acid thathad been previously purified by recrystallization from water wasdissolved in about three times its weight of water and hydrogenated at90 and 1500 can be distilled in a high vacuum. Its boiling point is160-164 C./0.3 mn'r, audits refractive index 2 This cyclic polyalcoholappears to be somewhat 'unstable above about 150 C., but appears to bequite stable at roomtemperature.

The following examples are given to further illustrate the invention.However, they are not to be considered asIimitin'gsaid invention'in anyway.

Example I A solution or 28.5 g. 0.2 mole) of koji'c acid, M. P.

153.5154.5 C., in 500 ml. of anhydrous ethanol'was hydrogenated at 1500p. s. i. and 110 C. for '4 hours using about 10 g. of Raney nickel asthe catalyst. The hydrogen uptake during this time corresponded to 0.6mole of hydrogen or three moles per mole of kojic acid. The vessel wascooled, the contents filtered and the solvent evaporated from theethanolic filtrate. There remained a dense viscous oil which wasdistilled in'vacuo; B. P 160'164 C./0.3 mm. The yield of distilled,product was 20.2 g. (68.3%). The hydroXyl value was determined by theacetic anhydride-pyridine method (Siggia Quantitative Organic Analysisvia Functional Groups,

- clear aqueous filtrate was concentrated invacuo.

John Wiley & Sons, Inc., 1949, p. 4) and found to be 48.7. Assumingthree hydroxyl groups per mole of hexahydrokojic acid, the calculatedvalue is 49.2.

Analysis.Calcd. for C T-T 0 C, 48.64; I-I,v 8.16.

Found: C, 48.61; H, 8.05. I

xqm z a A solution of 125 g. of kojic acid, which had beenrecrystallized from water, in 400 m1. of water was 'hydrogenated at 1500p. s; i. and -100 C. for 5 hours over 'Raney nickel. The vessel wascooled to room tempera.

Analysis.-Calcd. for C H O C, 48.64; H, 8.16; hy-- droyxl value, 49.2. 7Found: C, 48.32; H, 8.35; 'hydroxyl value, 50.5. What is claimed is:7 1. A process for preparing hexahydrokoji'c. acid com prisinghydrogenating kojic acid in a reaction inert solvent at a temperaturesubstantially. in the range 30 C. to C. at superatmospheric pressure inthe;

presence of Raney nickel catalyst.

' 2. A process as claimed in claim 1 wherein the hexa hydrokojic acid isrecovered from the reaction mixture 3. A process as claimed in claim 1wherein the'pressure is substantially in the range 500 to 2000 poundsper square inch.

4. A process for-preparing hexahydrokojic acid comprising the steps ofhydrogenating kojic acidin a reaction inert solvent at a temperaturesubstantially in the range of 30 C. to 110 C. at superatmosphericpressure and in the presence of a suspension of Raney nickel. catalyst,separating the catalyst from the resulting reaction product, treatingthe reaction product with a decolorizing agent, subsequently separatingthe decolorizing agent, and then recovering hexahydrokojic acid insubstantially pure form.

References Cited in the file of this patent Maurer: Berichte, 64, pp.2358-60 (1931).

1. A PROCESS FOR PREPARING HEXAHYDROKOJIC ACID COMPRISING HYDROGENATING KOJIC ACID IN A REACTION INERT SOLVENT AT A TEMPERATURE SUBSTANTIALLY IN THE RANGE 30*C. TO 110*C. AT SUPERATMOSPHERIC PRESSURE IN THE PRESENCE OF RANEY NICKEL CATALYST. 